The overarching objectives of this task include activities to advance the development and scientific understanding of a candidate malaria vaccine in humans. Malaria infects 200-300 million people worldwide and is a leading cause of death in young children in Sub-Saharan Africa. The Vaccine Research Center (VRC) has demonstrated high-level short-term protection in phase I clinical trials (VRC312) using an attenuated whole parasite vaccine administered intravenously. Furthermore, protection was found to be dependent on vaccine dose. An additional trial, VRC314, was initiated to extend these findings and further determine the effect of dose number, dose interval, and administration route on protection over a longer period of time. This trial is in progress with anticipated readouts by mid-2016. In order to further expand on such clinical studies, there is a critical need for understanding the immune correlates for long-term protection. Analytical methods such as RNAseq and advanced multiparameter flow cytometry analysis have been previously utilized to identify innate signatures and define biomarkers to help predict a protective immune response. Additional analyses contributing to the understanding of protective immune responses involve screening of antibodies for protective activity using in vitro experiments, and analyzing the microbiome in clinical patients to understand the impact of microbiota on immune responses following vaccination. Furthermore, sequence analysis of parasites during natural infection of immunized individuals may reveal immunological pressures exerted on Malaria parasites and advance the understanding of potential immune escape mechanisms. In addition to needing sophisticated mechanisms for investigating and interpreting immune responses during clinical studies, significant optimization of vaccine dose and regimen is required to maximize vaccine efficacy and assess long-term protection potential. Thus, in addition to ongoing clinical trials and the corresponding immune correlates analyses, additional clinical trials are anticipated to address the optimal dose and regimen required for high-level protection in response to a homologous or heterologous challenge in a United States clinical trial, and natural infection in an Africa clinical trial.